Zhang Yang, Yang Yang, Zeng Yuanyuan, Qu Qiuxia, Shen Dan, Mu Chuanyong, Lei Wei, Su Meiqin, Mao Jingyu, Gao Lirong, Liu Zeyi, Chen Cheng, Huang Jian-An
Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, China.
Institute of Respiratory Diseases, Soochow University, Suzhou, China.
Front Immunol. 2025 May 20;16:1553042. doi: 10.3389/fimmu.2025.1553042. eCollection 2025.
Immunotherapies targeting the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) have shown great promise for a subset of patients with non-small cell lung cancer (NSCLC). However, safe and robust combination therapies are still needed to bring the benefit to broader patient populations.
we performed treatment with PD-L1 antibody in Lewis lung carcinoma (LLC)-derived murine NSCLC model. Expression of B and T lymphocyte attenuator (BTLA) was detected during treatment. We evaluated the effects of the combination of anti-BTLA and anti-PD-L1 mAbs on tumor growth and overall survival of mice. In addition, distribution and function of immune cells were analyzed by flow cytometry. The role of BTLA in human and murine CD8 T cells and its impact on reversing exhausted phenotype of PD-1CD8 T cell by PD-L1 blockade were analyzed. Furthermore, we investigated expression and distribution of BTLA on lymphocytes in tumor microenvironment of different specimens from NSCLC patients.
There was no significant difference overall survival between anti-PD-L1 therapy and IgG in LLC-bearing mice, and BTLA expression was increased on CD8 T cells after PD-L1 antibody treatment. LLC-bearing mice treated with combination of anti-BTLA and anti-PD-L1 therapy had an improved overall survival than anti-BTLA or anti-PD-L1 alone. Compared to monotherapy with anti-BTLA or anti-PD-L1, mice treated with combination therapy demonstrated increased infiltration of CD8 and CD4 T cells, as well as increased expression of IFN-γ, TNF-α and Ki-67 in CD8 T cells. In addition, CD8 T cells co-expressing BTLA and PD-1 exhibited the most exhausted phenotype to resist PD-L1 blockade therapy. Furthermore, BTLACD8 T cells were abnormally increased in different specimens from NSCLC patients, and CD8 T cells expressing BTLA in NSCLC microenvironment were correlated with clinical response to anti-PD-1 therapy in NSCLC patients.
Our results show that BTLA and PD-1 cooperatively inhibit the activity of CD8 T cells and are associated with resistance to PD-1/PD-L1 pathway blockade in NSCLC patients. Anti-BTLA blockade enhances the antitumor efficacy of anti-PD-L1 therapy. Dual BTLA and PD-1/PD-L1 blockade should be further explored to elicit potent antitumor CD8 T-cell responses in NSCLC patients.
靶向程序性细胞死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）的免疫疗法已在一部分非小细胞肺癌（NSCLC）患者中显示出巨大潜力。然而，仍需要安全且有效的联合疗法，以使更多患者受益。
我们在源自Lewis肺癌（LLC）的小鼠NSCLC模型中用PD-L1抗体进行治疗。在治疗过程中检测B和T淋巴细胞衰减器（BTLA）的表达。我们评估了抗BTLA和抗PD-L1单克隆抗体联合使用对小鼠肿瘤生长和总生存期的影响。此外，通过流式细胞术分析免疫细胞的分布和功能。分析了BTLA在人和小鼠CD8 T细胞中的作用及其对通过PD-L1阻断逆转PD-1⁺CD8 T细胞耗竭表型的影响。此外，我们研究了NSCLC患者不同标本肿瘤微环境中淋巴细胞上BTLA的表达和分布。
在携带LLC的小鼠中，抗PD-L1治疗与IgG治疗的总生存期无显著差异，且PD-L1抗体治疗后CD8 T细胞上的BTLA表达增加。联合使用抗BTLA和抗PD-L治疗的携带LLC的小鼠总生存期比单独使用抗BTLA或抗PD-L1有所改善。与抗BTLA或抗PD-L1单药治疗相比，联合治疗的小鼠CD8和CD4 T细胞浸润增加，CD8 T细胞中IFN-γ、TNF-α和Ki-67的表达也增加。此外，共表达BTLA和PD-1的CD8 T细胞表现出最耗竭的表型，以抵抗PD-L1阻断疗法。此外，NSCLC患者不同标本中BTLA⁺CD8 T细胞异常增加，NSCLC微环境中表达BTLA的CD8 T细胞与NSCLC患者抗PD-1治疗的临床反应相关。
我们的结果表明，BTLA和PD-1协同抑制CD8 T细胞的活性，并与NSCLC患者对PD-1/PD-L1通路阻断的抗性相关。抗BTLA阻断增强了抗PD-L1治疗的抗肿瘤疗效。应进一步探索双重阻断BTLA和PD-1/PD-L1，以在NSCLC患者中引发有效的抗肿瘤CD8 T细胞反应。
